Leveraging decagonal in-silico strategies for uncovering IL-6 inhibitors with precision.

Interleukin-6 upregulation leads to various acute phase reactions such as local inflammation and systemic inflammation in many diseases like cancer, multiple sclerosis, rheumatoid arthritis, anemia, and Alzheimer's disease stimulating JAK/STAT3, Ras/MAPK, PI3K-PKB/Akt pathogenic pathways. Since no small molecules are available in the market against IL-6 till now, we have designed a class of small bioactive 1,3 - indanedione (IDC) molecules for inhibiting IL-6 using a decagonal approach computational studies. The IL-6 mutations were mapped in the IL-6 protein (PDB ID: 1ALU) from thorough pharmacogenomic and proteomics studies. The protein-drug interaction networking analysis for 2637 FFDA-approved drugs with IL-6 protein using Cytoscape software showed that 14 drugs have prominent interactions with IL-6. Molecular docking studies showed that the designed compound IDC-24 (-11.8 kcal/mol) and methotrexate (-5.20) bound most strongly to the 1ALU south asian population mutated protein. MMGBSA results indicated that IDC-24 (-41.78 kcal/mol) and methotrexate (-36.81 kcal/mol) had the highest binding energy when compared to the standard molecules LMT-28 (-35.87 kcal/mol) and MDL-A (-26.18 kcal/mol). These results we substantiated by the molecular dynamic studies in which the compound IDC-24 and the methotrexate had the highest stability. Further, the MMPBSA computations produced energies of -28 kcal/mol and -14.69 kcal/mol for IDC-24 and LMT-28. KDeep absolute binding affinity computations revealed energies of -5.81 kcal/mol and -4.74 kcal/mol for IDC-24 and LMT-28 respectively. Finally, our decagonal approach established the compound IDC-24 from the designed 1,3-indanedione library and methotrexate from protein drug interaction networking as suitable HITs against IL-6.

5-Fluorouracil enteric-coated nanoparticles for improved apoptotic activity and therapeutic index in treating colorectal cancer.

5-Fluorouracil (5-FU) is one among the anti-cancer agents in FOLFORINOX treatment along with oxaliplatin and irinotecan for the treatment of colorectal cancer. Despite its potential activity on the tumor cells, it lacks site specificity partly attributed by its biodistribution to healthy cells resulting in toxic effects to healthy cells. Therefore, we have formulated 5-fluorouracil enteric-coated nanoparticles (5-FUEC) to localize the drug in the colon area that enables its prolonged presence in target area in a sustained manner. The current work emphasizes on enhanced anti-cancer activity of 5-FUEC sequencing its apoptotic activity on HCT 116 colorectal cancer cell lines in vitro. MTT assay exhibited 5.5-fold decrease in IC50 value of nanoparticles comparable to 5-FU. Nuclear fragmentation with irregular edges in nucleus of cells justified its improved activity. Furthermore, flow cytometric analysis confirms the majority of cells gated in early apoptotic (39.75%) and late apoptotic phase (36.25%). Acridine orange/ethidium bromide staining (AO/EB) exhibited cells with red fluorescence (indicating apoptosis) comparable to the control and 5-FU. γ-Scintigraphic studies determined the applicability and feasibility of the enteric coating with mean gastric emptying time, mean intestinal transit time and mean colon arrival time of 1.89 ± 0.03, 2.15 ± 0.05 and 4.03 ± 0.27 h, respectively. Moreover, nanoparticulate approach was found significant in reducing tumor size and volume in xenograft tumor models in vivo along with sustained release. These superior anti-cancer activities exhibited by 5-FUEC indicated that it could be a potential alternative to chemotherapy for colorectal cancer.

Formulation and optimization of oxaliplatin immuno-nanoparticles using Box-Behnken design and cytotoxicity assessment for synergistic and receptor-mediated targeting in the treatment of colorectal cancer.

Conventional chemotherapy majorly lacks clinical application attributed to its inspecificity, adverse effects and inability to penetrate into tumor cells. Hence, the aim of the study was to prepare oxaliplatin solid lipid nanoparticles (OP-SLN) by microemulsion method optimizing it by Box-Behnken design and then covalently conjugated to TRAIL (CD-253) monoclonal antibody (TR-OP-SLN) for targeting colorectal cancer cells. The optimized OP-SLN3 has shown an appreciable particle size (121 ± 1.22 nm), entrapment efficiency (78 ± 0.09%) and drug loading (32 ± 1.01%). Fluorescence study and the Bradford assay further confirmed the binding of the protein. A 1.5-fold increase in cytotoxicity of immuno-nanoparticles (4.9 µM) was observed.

Screening of Caesalpinia bonduc leaves for antipsoriatic activity.

ETHNOPHARMACOLOGICAL RELEVANCE: Leaves of Caesalpinia bonduc (L.) Roxb. (Caesalpiniaceae) have been used by traditional Siddha healer of Malabar region for psoriasis treatment. AIM OF THE STUDY: To evaluate the Caesalpinia bonduc decoction (CBD), Caesalpinia bonduc hydroalcoholic extract (CBHA) for antipsoriatic activity. MATERIALS AND METHODS: Mouse tail test for psoriasis was used for the evaluation of antipsoriatic activity. Extracts were tested at a dose of 500 mg/kg b.w. and fractions at 250 mg/kg b.w. in Swiss albino mice. Parameters studied in the mouse tail test were changes in epidermal thickness and percentage orthokeratotic values. In vitro antiproliferant assay on HaCaT cell lines and in vitro lipoxygenase inhibition were also carried out. RESULTS: Butanol fraction of Caesalpinia bonduc hydroalcoholic extract (CBHAB) and water fraction of Caesalpinia bonduc hydroalcoholic extract (CBHAW) produced significant orthokeratosis (p<0.001). In relative epidermal thickness, a significant (p<0.05) reduction with respect to control was observed in groups treated with retinoic acid, CBD, butanol fraction of Caesalpinia bonduc decoction (CBDB), water fraction of Caesalpinia bonduc hydroalcoholic extract (CBHAW). Maximum antiproliferant activity was shown by CBHA (IC(50), 77.5±12.7 µg/ml). In lipoxygenase inhibition assay, water fraction of Caesalpinia bonduc decoction (CBDW) showed maximum activity with an IC(50) value of 164.71±4.57 µg/ml. CONCLUSIONS: Among all the tested samples only CBHAW showed good activity in the mouse tail test, antiproliferant activity in HaCaT cells and lipoxygenase inhibition assay. Other extracts and fractions showed varying degrees of activity. The present study supports the traditional use of Caesalpinia bonduc leaves for psoriasis treatment.

Hepatoprotective activity of petroleum ether, diethyl ether, and methanol extract of Scoparia dulcis L. against CCl4-induced acute liver injury in mice.

OBJECTIVES: The present study was aimed at assessing the hepatoprotective activity of 1:1:1 petroleum ether, diethyl ether, and methanol (PDM) extract of Scoparia dulcis L. against carbon tetrachloride-induced acute liver injury in mice. MATERIALS AND METHODS: The PDM extract (50, 200, and 800 mg/kg, p.o.) and standard, silymarin (100 mg/kg, p.o) were tested for their antihepatotoxic activity against CCl4-induced acute liver injury in mice. The hepatoprotective activity was evaluated by measuring aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, and total proteins in serum, glycogen, lipid peroxides, superoxide dismutase, and glutathione reductase levels in liver homogenate and by histopathological analysis of the liver tissue. In addition, the extract was also evaluated for its in vitro antioxidant activity using 1, 1-Diphenyl-2-picrylhydrazyl scavenging assay. RESULTS: The extract at the dose of 800 mg/kg, p.o., significantly prevented CCl4-induced changes in the serum and liver biochemistry (P < 0.05) and changes in liver histopathology. The above results are comparable to standard, silymarin (100 mg/kg, p.o.). In the in vitro 1, 1-diphenyl-2-picrylhydrazyl scavenging assay, the extract showed good free radical scavenging potential (IC 50 38.9 +/- 1.0 mug/ml). CONCLUSIONS: The results of the study indicate that the PDM extract of Scoparia dulcis L. possesses potential hepatoprotective activity, which may be attributed to its free radical scavenging potential, due to the terpenoid constituents.